Illumigen is pursuing an alternative genetics-driven approach to drug discovery that relies on the identification of mutations associated with health rather than disease. Beneficial or health-inducing mutations, like most disease-causing mutations, are expected to negatively impact gene function in a way that can be mimicked by an inhibitory drug. This Phase I application encompasses the first part of our program to identify genetic mutations that confer resistance to hepatitis C infection and to develop new drugs that mimic the beneficial effects of these mutations. We describe in this Phase I proposal a candidate gene based allele association study to investigate the genetic determinants of HCV resistance. Case and control subjects are being selected from two high-risk populations (hemophiliacs and injecting drug users). Cases are defined as those subjects with significant documented exposure to HCV who remain uninfected. A prioritized list of candidate genes will be interrogated in the case and control populations using targeted DNA sequencing. Polymorphism discovery will focus on the exons, exon/intron boundaries, and untranslated regions of each candidate gene. Nine million phred Q about 20 bases of data will be generated during Phase I. Methods for data analysis and control of population substructure are described.